Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors.
OBJECTIVE
BI 2536 is a novel, potent, and highly specific inhibitor of polo-like kinase 1 (Plk1), which has an essential role in the regulation of mitotic progression. The aim of this trial was to identify the maximum tolerated dose (MTD) of BI 2536 and to determine the safety, pharmacokinetics, and antitumor activity in patients who had advanced solid tumors.


METHODS
This phase I trial followed an open label, toxicity-guided, dose-titration design. Single doses of BI 2536 (25 to 250 mg) were administered as a 1-hour intravenous infusion; patients who experienced clinical benefit were eligible for additional treatment courses. Safety and pharmacokinetics were investigated. Tumor response was evaluated according to Response Evaluation Criteria in Solid Tumors Group guidelines.


RESULTS
The MTD was defined at 200 mg in a total of 40 patients entered; reversible neutropenia constituted the dose-limiting toxicity (DLT) and the most frequent adverse event at the MTD (grade 3 to 4; 56%). Nausea (52%), fatigue (52%), and anorexia (44%) also were common and were mostly of mild to moderate intensity (Common Terminology Criteria of Adverse Events <or= grade 2). One patient experienced a transient partial response. At doses equal to or greater than the MTD, 23% of patients experienced disease stabilization for 3 or more months. Dose-proportional increases in the maximum plasma concentration and total exposure were observed. BI 2536 showed a high total clearance and high distribution into tissue.


CONCLUSIONS
The MTD of BI 2536 when administered as a single-dose, 1-hour infusion was 200 mg; BI 2536 was well tolerated and showed a favorable pharmacokinetic profile. Antitumor activity of BI 2536 was observed.
Mross
Klaus
K
Tumor Biology Center at the Albert-Ludwigs-University Freiburg, Breisacherstrasse 117, D-79106, Freiburg, Germany. mross@tumorbio.uni-freiburg.de
Frost
Annette
A
Steinbild
Simone
S
Hedbom
Susanne
S
Rentschler
Jochen
J
Kaiser
Rolf
R
Rouyrre
Nicolas
N
Trommeshauser
Dirk
D
Hoesl
Cornelia E
CE
Munzert
Gerd
G
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536